Population shift mechanism for partial agonism of AMPA receptor
Population shift mechanism for partial agonism of AMPA receptor
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AMPA 受体部分激动的群体转移机制
DOI：
10.1016/j.bpj.2018.11.3122
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Sugita Y.
中科院分区：
文献类型：
--
作者：
Oshima H;Re S;Sakakura M;Takahashi H;Sugita Y.
α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionic酸(AMPA)离子型谷氨酸受体在中枢神经系统中介导快速兴奋性神经传递，其功能障碍与神经系统疾病有关。谷氨酸与AMPA受体的配体结合域(LBD)结合可诱导受体跨膜区的通道开放。T686A突变降低了谷氨酸的功效，使谷氨酸表现为部分激动剂。野生型和突变型LBD的晶体结构非常相似，不能解释观察到的行为。为了阐明诱导T686A突变体部分激活性的分子机制，我们使用副本交换伞采样模拟计算了控制GluA2 LBD闭合的自由能景观。在模拟过程中，突变体中出现了一种在晶体结构中没有观察到的半封闭状态。在这种状态下，由于叶间氢键的断裂，LBD裂隙轻微打开，降低了通道打开的效率。LBD的闭合态和半闭合态之间的能量差很小，这两个态之间的跃迁会因热涨落而发生。显然，谷氨酸与T686A突变体的结合导致群体从封闭状态转变为半封闭状态，这解释了AMPA受体的部分激动性。
α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionic acid (AMPA) ionotropic glutamate receptors mediate fast excitatory neurotransmission in the central nervous system, and their dysfunction is associated with neurological diseases. Glutamate binding to ligand-binding domains (LBDs) of AMPA receptors induces channel opening in the transmembrane domains of the receptors. The T686A mutation reduces glutamate efficacy so that the glutamate behaves as a partial agonist. The crystal structures of wild-type and mutant LBDs are very similar and cannot account for the observed behavior. To elucidate the molecular mechanism inducing partial agonism of the T686A mutant, we computed the free-energy landscapes governing GluA2 LBD closure using replica-exchange umbrella sampling simulations. A semiclosed state, not observed in crystal structures, appears in the mutant during simulation. In this state, the LBD cleft opens slightly because of breaking of interlobe hydrogen bonds, reducing the efficiency of channel opening. The energy difference between the LBD closed and semiclosed states is small, and transitions between the two states would occur by thermal fluctuations. Evidently, glutamate binding to the T686A mutant induces a population shift from a closed to a semiclosed state, explaining the partial agonism in the AMPA receptor.